Background

This phase I study addresses the question of the maximum tolerated dose (MTD) when Taxol is adminstered with AHFRT.

Unresectable locally advanced head and neck squamous cell carcinomas (SCCa) have a poor prognosis with radiation therapy (RT) alone in standard once-daily fractionation. Many have attempted to alter the frequency, length of treatment and total dose in order to improve the outcome. There have been data to support some improvement in local control with these adjustments in the RT.

Chemotherapy (ChT) had historically been an unproven entity in the treatment of head and neck carcinomas. Recently, many studies have come to light, demonstrating the efficacy of ChT when combined with radiotherapy (RT). In resectable locally advanced disease, there have been two major randomized trials of organ preservation (VA Laryngeal Preservation along with a European trial) that have demonstrated the efficacy of induction ChT in head and neck SCCa. Another randomized trial from the Cleveland Clinic demonstrated the superiority of concurrent ChT plus RT over RT alone in the locally advanced head neck cancer. A study from Duke University demonstrated superior local control and survival for the combined modality (RT + ChT) arm in a randomized trial of accelerated hyperfractionated RT (AHFRT) versus AHFRT with ChT. All four trials mentioned above utilized 5-FU and cisplatin as their ChT regimen. Acute toxicities of treatment were increased with concurrent ChT/RT, occasionally causing treatment delays -- possibly compromising local control and overall outcome. Thus, there has been a push to pursue other ChT agents with the same if not better efficacy and less toxicity.

Hydroxyurea and carboplatin have been utilized in combination with other ChT agents for head and neck SCCa. In the dawning age of the taxanes, hope has been generated for improvement of the above response and survival rates. Multiple studies of paclitaxel (Taxol) have been ongoing. Reports have demonstrated that the standard effective systemic dose is 175 - 200 mg/m2. In combination with concurrent RT, Taxol doses must be tempered, since there has been documented enhancement of radiation toxicities with the addition of the drug. Taxol was the focus of this phase I trial from the Hospital of the University of Pennsylvania. The effects from a single administration of Taxol can last up to several days. The theory was that prolonging the infusion of Taxol would increase the duration of efficacy or radiosensitization. Some preclinical data have suggested this to be true along with clinical studies in breast and lung cancer. The goal of this phase I trial was to determine the maximum tolerated dose (MTD) of 96-hour infusional Taxol with concurrent concomitant boost RT regimen.

Patients and Methods

Patients eligible for this phase I trial were histopathologically confirmed to have non-metastatic head and neck SCCa that were deemed unresectable based on primary tumor extension, and/or neck node fixation.

The RT was given with a megavoltage machine using daily fractionation of 2 Gy per day initially to 40 Gy. Cone-down fields with spinal cord shielding followed with twice-a-day fractionation of 1.6 Gy each. The planned total dose was 70 - 72 Gy to areas of gross disease.

The ChT consisted of single agent Taxol given over 96 hours. This was given on weeks 1 and 5 of the RT. The dose escalation began at 40 mg/m2/96 hours and increased by 40 mg/m2/96 hours for every dose level. Dose level 2A 100 mg/m2/96 hours was created after reaching dose level 3 (120 mg/m2/96 hours) and excessive toxicity was reported. Details will be explained below.

Results

Thirteen patients were enrolled. Patient characteristics in Table 1 of the article demonstrated that most were of the T4 (local extension to adjacent structures) and N2 (large ipsilateral or bilateral nodal disease) variety. Most all cases were oropharynx and hypopharynx (pyriform sinus). Median RT time was 42 days, and median dose was 71 Gy. Three patients completed dose level 1 (40-mg/m2/96 hours), 5 were entered into level 2 (80 mg/m2/96 hours), 2 in level 3 (120 mg/m2/96 hours) and 3 into level 2A (100 mg/m2/96 hours).

There was a high compliance with the planned treatment. Only one patient did not complete the planned RT -- the patient had progressive disease (defined asextension of disease outside of the treatment portal or greater than 25% enlargement in the tumor) after 61 Gy. All but one patient completed the planned 2 cycles of Taxol -- the patient developed a grade 2 allergic reaction on the second cycle.

Toxicities were listed in Table 2 of the article. No grade 5 (treatment-related deaths) toxicities were seen. Grade 3 mucositis predominated (10 of 13 patients) and were seen at all dose levels (attributable to the accelerated nature of the RT). The dose limiting toxicities were seen in both dose level 3 patients (one had grade 4 dermatitis and the other had grade 4 mucositis and febrile neutropenia). Thus, MTD was exceeded and the dose level 2A was created. The 3 patients enrolled at this dose level had no grade 4 toxicities.

Though the design of this trial was not focused on efficacy, analysis demonstrated a very promising result. Complete responses were seen in 8 of the patients treated. Partial responses were seen in 4 of the remaining 5 patients. Two of the complete responders relapsed, while overall, 4 have died of their disease. The median follow-up was 12 months. The progression-free survival rate and overall survival rate at 1 year was 63% and 73% respectively.

Discussion and Critique

The MTD of 96-hour infusional Taxol was 100 mg/m2/96 hours based on this phase I trial. All of the grade 3 - 4 acute toxicities were reversible. No neurotoxicity was seen, but late onset myelopathies may not yet have developed in this relatively short follow-up. Once weekly doses of Taxol have demonstrated a MTD of 30 mg/m2/week. A current head and neck SCCa protocol utilizes this weekly dose with the addition of cisplatin in one arm of their prospective randomized trial. Similar Taxol delivery methods (prolonged infusion over 96 - 120 hours) have been used in combination with standard once-a-day radiation or hyperfractionation with longer RT treatment duration. This phase I study is only one of its kind to use the prolonged infusion of Taxol and accelerated RT. This dosage of Taxol seems to be very efficacious relative to other non-Taxol containing regimens. Though a very intense regimen, the outcome seems to justify the aggressiveness of the approach. The obvious next step is a phase II trial to demonstrate efficacy, since it seems very promising preliminarily despite the short follow-up and small patient numbers.